Dong Sup Kwag

Electrostatic charge conversion processes in engineered tumor-identifying polypeptides for targeted chemotherapy.

One of the current challenges in cancer chemotherapy is the ultra-sensitive identification of in vivo tumors. Herein, we report a new class of tumor-identifying polypeptides that can home in on in vivo tumors via an electrostatic charge conversion process occurring in the acidic milieu of a verity of tumors, which can be distinguished from receptor-interacting conventional tumor-homing peptides. We exploit the chemical coupling between polypeptides and therapeutic objects (drugs or particles) to carry out an antitumor study in nude mice, and find a significant increase in the efficiency of polypeptide-tagged objects in tumor uptake and inhibition, which is more significant than any known tumor-homing peptide system thus far developed.

Photodynamic therapy using glycol chitosan grafted fullerenes.

Glycol chitosan (GC)-grafted fullerene (GC-g-C(60)) conjugates were developed for use in photodynamic therapy of tumor cells. GC-g-C(60) was synthesized in anhydrous benzene/dimethylsulfoxide (DMSO) co-solvent via the chemical conjugation of free amine groups of GC to CC double bonds of C(60). The GC-g-C(60) with 5×10(-4) C(60) molecules per one repeating unit of GC was soluble in water. As C(60) molecules conjugated to GC increased to 0.16 molecules per one repeating unit of GC, GC-g-C(60) started to form supramolecular assemblies (∼30 nm) stabilized in phosphate buffer saline (PBS, 150 mM, pH 7.4). Upon 670 nm light illumination, photo-responsive properties of GC-g-C(60) allowed tremendous singlet oxygen generation in tumor cells for super phototoxicity. GC-g-C(60) also showed highly increased tumor accumulation ability for in vivo tumor of KB tumor-bearing nude mice. It is expected that our GC-g-C(60) conjugate may be a good candidate for in vivo photodynamic therapy in various malignant tumor cells.

Acid pH-activated glycol chitosan/fullerene nanogels for efficient tumor therapy

Glycol chitosan (GC) grafted with 2,3-dimethylmaleic acid (DMA) and fullerene (C60) conjugates (GC-g-DMA-g-C60) were developed for use in a photosensitizer prodrug. GC-g-DMA-g-C60 was prepared via the simple two-step chemical grafting reactions of (i) DMA to free amine groups of GC and (ii) hydroxyl groups of GC-g-DMA to ππ carbon bonds of C60. This conjugate was self-assembled to form polysaccharidic nanogels consisting of a hydrophilic block (GC and DMA) and a hydrophobic block (C60). Here, GC-g-DMA-g-C60 nanogels also formed multi-nanogel aggregates due to the electrostatic interaction between the pendant carboxylic acid group (due to the DMA) and residual free amine group of GC at pH 7.4. Interestingly, the nanogel aggregates can be disintegrated at pH 5.0 due to the reduction of electrostatic interaction resulting from the cleavage of the DMA blocks at pH 5.0. Upon 670nm light illumination, photo-responsive properties of the nanogel aggregates allowed different singlet oxygen generation according to the pH condition: the reduced singlet oxygen generation (due to increased photo-interference effect between C60 molecules close-packed in nanogel aggregates) at pH 7.4, but the elevated singlet oxygen generation (due to the disintegration of nanogel aggregates) at pH 5.0. GC-g-DMA-g-C60 nanogel aggregates responds to pH 5.0 (approximately endosomal pH) can be a good candidate for endosomal pH targeting and in vivo photodynamic therapy in various malignant tumor cells.

Multifunctional poly (lactide-co-glycolide) nanoparticles for luminescence/magnetic resonance imaging and photodynamic therapy

Poly (lactide-co-glycolide) (PLGA) coupled with methoxy poly (ethylene glycol) (mPEG) or chlorin e6 (Ce6) was synthesized using the Steglich esterification method. PLGA-linked mPEG (PLGA-mPEG), PLGA-linked Ce6 (PLGA-Ce6), and Fe(3)O(4) were utilized to constitute multifunctional PLGA nanoparticles (∼160 nm) via the multi-emulsion W(1)/O/W(2) (water-in-oil-in-water) method. The photo-sensitizing properties of Ce6 molecules anchored to PLGA nanoparticles enabled in vivo luminescence imaging and photodynamic therapy for the tumor site. The encapsulation of Fe(3)O(4) allowed high contrast magnetic resonance (MR) imaging of the tumor in vivo. Overall, PLGA nanoparticles resulted in a significant tumor volume regression for the light-illuminated KB tumor in vivo and enhanced the contrast at the tumor region, compared to that of Feridex(®) (commercial contrast agent).

Multifunctional nano-sized fullerenes for advanced tumor therapy

There is an increasing demand for the development of functional photosensitizing nano-sized drugs. Fullerene, one of the new carbon molecules, has been considered to be a useful and versatile material for this purpose. Notably, fullerenes are water-insoluble, and they readily aggregate in aqueous solution. Therefore, fullerenes usually have been coupled with water-soluble, biocompatible, biodegradable polymers (e.g., polysaccharides, proteins, and other functional polymers), achieving their improved water-solubility and biocompatible properties. In particular, when fullerenes are paired with tumor-targeting ligands or stimuli-responsive polymers, these conjugates exhibit enhanced tumor recognition ability and improved tumor inhibition. Some groups encapsulated fullerenes into liposomes or nanoemulsions for various pharmaceutical purposes. This review provides an in-depth understanding of fullerene/polymer nanoparticles for effective fullerene-mediated tumor therapy.

Facile Synthesis of Multimeric Micelles

Bringing it all together: Synthesis of a dimeric micelle (see scheme) is shown to produce specifically linked Janus-like micelles. The reaction conditions for dimeric micelle formation were optimized and the resulting micelles characterized. Trimeric, tetrameric, and multimeric micelles were also synthesized using the same technique.

Acidic pH-stimulated tiotropium release from porous poly(lactic-co-glycolic acid) microparticles containing 3-diethylaminopropyl-conjugated hyaluronate

In this study, we developed porous poly(lactide-co-glycolide) (PLGA) microparticles (PM) exhibiting pH-activated drug release properties. The PMs were prepared via the water-in-oil-in-water (W1/O/W2) multi-emulsion method using PLGA, 3-diethylaminopropyl amine (DEAP)-conjugated hyaluronate (HA) (HA-DEAP), and an anti-cholinergic model drug (tiotropium). Here, HA-DEAP was incorporated into the PMs; it acted as a drug release activator, accelerating drug release. In vitro drug release studies revealed that the tiotropium was released from the PMs as their pores were destabilized by eletrostatic interactions between the carboxyl groups (negatively charged) of the HA molecules and the tertiary amine groups (positively charged) of the DEAP moieties under acidic environments. This PLGA microparticle system, which contains a HA-DEAP, could provide unique advantages in treating chronic obstructive pulmonary disease (COPD) with chronic respiratory acidosis.

Facile synthesis of partially uncapped liposomes.

Sophisticated control of the assembly of nano-sized structures to achieve desired properties is one of the most efficient techniques in drug carrier design. In this study, we hypothesized that under magnetic shear stress, high-density superparamagnetic Fe3O4 nanoparticles dispersed in a liposome would apply a high load in a particular direction to a liposome membrane and ultimately generate open lipid bilayer holes. Indeed, the designed experimental conditions enabled the formation of one or multiple open pore sites in liposome membranes. With this evidence, open lipid bilayer holes in liposome membranes were further used as open entrances for proteins (bovine serum albumin or insulin) into the liposomes prior to the natural recovery (i.e., closing) of the lipid bilayer holes. This trial will provide potential opportunities for the engineering of functional liposomes for protein drug delivery.

Gas-forming liposomes prepared using a liposomal magnetoporation method

In this study, we report a gas-forming drug carrier engineered using the liposomal magnetoporation method. The liposomes that were magnetoporated under a magnetic shear stress possessed an opened lipid bilayer hole. A photosensitizing model drug (chlorin e6: Ce6) and 1H-1H-2H-perfluoro-1-hexene (PFH, as a volatile gas-forming agent) were efficiently loaded into the opened holes of the magnetoporated liposomes. PFH in the liposomes is vaporized at 50°C and can initiate liposome destabilization. The experimental results demonstrated that the liposomes were destabilized at 50°C efficiently released Ce6 and enhanced Ce6-mediated phototoxicity against KB tumor cells. As a result, these liposomes induced a significantly increased in vitro and in vivo photodynamic tumor inhibition.

Immense Insulin Intestinal Uptake and Lymphatic Transport Using Bile Acid Conjugated Partially Uncapped Liposome

We provide immense insulin absorption from the gastrointestinal tract, combining apical sodium-dependent bile acid transporter-mediated intestinal uptake and the lymphatic transport pathway. This strategy has proven to employ chondroitin sulfate- g-taurocholic acid coated, insulin-loaded partially uncapped liposome (IPUL-CST) for type 1 diabetes mellitus (T1DM) treatment. The loading efficiency of insulin in IPUL-CST increased significantly from 33% to 75% via the partially uncapped liposome preparation method. Moreover, the IPUL-CST revealed an improved insulin protection efficacy in GIT simulated pH and digestive enzyme conditions. The high dose of IPUL-CST in the small intestine was detected 4 h post-oral administration using ex vivo optical imaging and fluorescence intensity. The IPUL-CST exhibited significantly enhanced intestinal absorption (oral bioavailability, 34%; Tmax, 9 h) and reduced blood glucose levels for 16 h in T1DM. The results demonstrated that the new investigated IPUL-CST is a promising carrier for oral insulin delivery.